CN1358187A - New compounds - Google Patents

Abstract

The present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts, which compounds inhibit carboxypeptidase U and thus can be used in the prevention and treatment of diseases associated with carboxypeptidase U. In further aspects, the invention relates to compounds of the invention for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a pharmaceutically acceptable salt or solvate thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above.

Description

new compound

Field of the invention

The present invention relates to novel compounds and pharmaceutically acceptable salts thereof, which compounds inhibit alkaline carboxypeptidase, more precisely, inhibit carboxypeptidase U, so that they can be used in the prophylaxis and treatment wherein the inhibition of carboxypeptidase U is beneficial disease. In other aspects, the invention relates to compounds of the invention for use in therapy; processes for the preparation of said novel compounds; pharmaceutical compositions comprising at least one compound of the invention or a pharmaceutically acceptable salt thereof as an active ingredient; and Use of said active compound for the manufacture of a medicament for medical use as described above.

Background of the invention

Fibrinolysis is the result of a series of enzymatic reactions via plasmin that lead to the degradation of fibrin. Activation of plasminogen is a key process in fibrinolysis. The cleavage of plasminogen to produce plasmin is accomplished by plasminogen activator, tissue plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA). Initial plasmin degradation of fibrin produces a carboxy-terminal lysine residue that serves as a high-affinity binding site for plasminogen. Since fibrin-linked plasminogen is more readily activated to plasmin than free plasminogen, this mechanism provides a positive feedback regulation of fibrinolysis.

One of the endogenous inhibitors of fibrinolysis is carboxypeptidase U (CPU). CPU is also known as plasma carboxypeptidase B, active thrombin-activatable fibrinolysis inhibitor (TAFIa), carboxypeptidase R, and inducible carboxypeptidase activity. CPU is formed from its precursor procarboxypeptidase U (pro CPU) by the action of proteolytic enzymes such as thrombin, thrombin-thrombomodulin complex, or plasmin during blood coagulation and fibrinolysis. CPU cleaves basic amino acids at the carboxyl terminus of fibrin fragments. The loss of the carboxy-terminal lysine and thus the lysine binding site for plasminogen is then used to inhibit fibrinolysis.

Potent carboxypeptidase U inhibitors are expected to aid in fibrinolysis by inhibiting the loss of the lysine binding site for plasminogen and thus increasing the rate of plasmin formation.

2-Mercaptomethyl-3-guanidinoethylthiopropionic acid has been reported as an inhibitor of carboxypeptidase N. More recently, this compound has been shown to inhibit CPU, Hendriks, D. et al., Biochimica et Biophysica Acta, 1034 (1990) 86-92.

Guanidinoethylmercaptosuccinic acid has been reported as an inhibitor of carboxypeptidase N. More recently, this compound has been shown to inhibit CPU, Eaton, D.L. et al., The Journal of Biological Chemistry, 266 (1991) 21833-21838.

The present invention is disclosed

It has surprisingly been found that the compounds of the formula I are particularly effective as inhibitors of carboxypeptidase U and are therefore useful as medicaments for the treatment or prophylaxis of diseases in which inhibition of carboxypeptidase U is beneficial.

Thus, in one aspect, the present invention relates to compounds of general formula I or a pharmaceutically acceptable salt or solvate thereof, or a solvate of the salt, wherein _R represents,

C ₁ -C ₆ alkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

Cycloalkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

A heterocyclic group containing at least one nitrogen atom;

Containing at least one heteroatom selected from S or O and a heterocyclic group substituted by one or more basic groups such as amino, amidino and/or guanidino;

基团或 基团或

基团，R₅代表H、C₁-C₆烷基或芳基，R₆代表C₁-C₆烷基、芳基、环烷基、杂环基或任选N-取代的H₂N-C(Z)-CONH-C(Z)-或H₂N-C(Z)-基团，R₇代表H或C₁-C₆烷基，X代表O、S、SO、SO₂、C(Z)₂、N(Z)、NR₇SO₂、SO₂NR₇、NR₇CO或CONR₇，Y代表O、N(Z)、S、C(Z)₂或单键，Z独立代表H、C₁-C₆烷基、芳基、环烷基或杂环基，条件是当X代表O、S、SO、SO₂、N(Z)、NR₇SO₂、SO₂NR₇或NR₇CO时，则Y代表C(Z)₂或单键。Or aryl substituted by one or more basic groups such as amino, amidino and/or guanidino, _R represents H, acyl, amido, alkyl, alkylcarbamoyl, alkylthio, alkoxy Aroyl, aroylamino, aryloxy, arylthio, amidino, amino, aryl, carbamoyl, carboxyl, cyano, cycloalkyl, formyl, guanidino, halogen, heterocyclyl, Hydroxy, oxo, nitro, thiol, Z ₂ N-CO-O-, ZO-CO-NZ- or Z ₂ N-CO-NZ-, R ₃ represents COOR ₅ , SO(OR ₅ ), SO ₃ R ₅ , P=O(OR ₅ ) ₂ , B(OR ₅ ) ₂ , P=OR ₅ (OR ₅ ) or isosteres of tetrazole or any carboxylic acid, R ₄ represents

group or group or

Group, R ₅ represents H, C ₁ -C ₆ alkyl or aryl, R ₆ represents C ₁ -C ₆ alkyl, aryl, cycloalkyl, heterocyclyl or optionally N-substituted H ₂ NC (Z)-CONH-C(Z)-or H ₂ NC(Z)-group, R ₇ represents H or C ₁ -C ₆ alkyl, X represents O, S, SO, SO ₂ , C(Z) _2. N(Z), NR ₇ SO ₂ , SO ₂ NR ₇ , NR ₇ CO or CONR ₇ , Y represents O, N(Z), S, C(Z) ₂ or a single bond, Z independently represents H, C ₁ -C ₆ alkyl, aryl, cycloalkyl or heterocyclyl, provided that when X represents O, S, SO, SO ₂ , N(Z), NR ₇ SO ₂ , SO ₂ NR ₇ or NR ₇ CO , then Y represents C(Z) ₂ or a single bond.

Preferred compounds according to the invention are those compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a salt thereof, wherein _R represents,

C ₁ -C ₆ alkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

Cycloalkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

A heterocyclic group containing at least one nitrogen atom;

Containing at least one heteroatom selected from S or O and a heterocyclic group substituted by one or more basic groups such as amino, amidino and/or guanidino;

基团或

基团，R₅代表H、C₁-C₆烷基或芳基，R₆代表C₁-C₆烷基、芳基、环烷基、杂环基或任选N-取代的H₂N-C(Z)-CONH-C(Z)-或H₂N-C(Z)-基团，R₇代表H或C₁-C₆烷基，X代表C(Z)₂，Y代表O、N(Z)、S、C(Z)₂或单键，Z独立代表H、C₁-C₆烷基、芳基、环烷基或杂环基。Or aryl substituted by one or more basic groups such as amino, amidino and/or guanidino, _R represents H, acyl, amido, alkyl, alkylcarbamoyl, alkylthio, alkoxy Aroyl, aroylamino, aryloxy, arylthio, amidino, amino, aryl, carbamoyl, carboxyl, cyano, cycloalkyl, formyl, guanidino, halogen, heterocyclyl, Hydroxy, oxo, nitro, thiol, Z ₂ N-CO-O-, ZO-CO-NZ- or Z ₂ N-CO-NZ-, R ₃ represents COOR ₅ , R ₄ represents group or

group or

Group, R ₅ represents H, C ₁ -C ₆ alkyl or aryl, R ₆ represents C ₁ -C ₆ alkyl, aryl, cycloalkyl, heterocyclyl or optionally N-substituted H ₂ NC (Z)-CONH-C(Z)-or H ₂ NC(Z)-group, R ₇ represents H or C ₁ -C ₆ alkyl, X represents C(Z) ₂ , Y represents O, N(Z) ), S, C(Z) ₂ or single bond, Z independently represents H, C ₁ -C ₆ alkyl, aryl, cycloalkyl or heterocyclic group.

More preferred compounds according to the present invention are those compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a salt thereof, wherein _R represents,

Cycloalkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

A heterocyclic group containing at least one nitrogen atom;

基团，R₅代表H、C₁-C₆烷基或芳基，R₆代表C₁-C₆烷基、芳基、环烷基、杂环基或任选N-取代的H₂N-C(Z)-CONH-C(Z)-或H₂N-C(Z)-基团，X代表C(Z)₂，Y代表O或C(Z)₂，Z独立代表H或C₁-C₆烷基。Containing at least one heteroatom selected from S or O and a heterocyclic group substituted by one or more basic groups such as amino, amidino and/or guanidino; R ₂ represents H, C ₁ -C ₃ alkyl, Amino, halogen or hydroxyl, R ₃ represents COOR ₅ , R ₄ represents

Group, R ₅ represents H, C ₁ -C ₆ alkyl or aryl, R ₆ represents C ₁ -C ₆ alkyl, aryl, cycloalkyl, heterocyclyl or optionally N-substituted H ₂ NC (Z)-CONH-C(Z)-or H ₂ NC(Z)-group, X represents C(Z) ₂ , Y represents O or C(Z) ₂ , Z independently represents H or C ₁ -C ₆ alkyl.

Other more preferred compounds according to the present invention are those compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a salt thereof, wherein _R represents,

Cycloalkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

A heterocyclic group containing at least one nitrogen atom;

基团，R₅代表H、C₁-C₆烷基或芳基，R₇代表H或C₁-C₆烷基，X代表C(Z)₂，Y代表C(Z)₂或单键，Z独立代表H或C₁-C₆烷基。Containing at least one heteroatom selected from S or O and a heterocyclic group substituted by one or more basic groups such as amino, amidino and/or guanidino; R ₂ represents H, C ₁ -C ₃ alkyl, Amino, halogen or hydroxyl, R ₃ represents COOR ₅ , R ₄ represents

Group, R ₅ represents H, C ₁ -C ₆ alkyl or aryl, R ₇ represents H or C ₁ -C ₆ alkyl, X represents C(Z) ₂ , Y represents C(Z) ₂ or a single bond , Z independently represents H or C ₁ -C ₆ alkyl.

Other more preferred compounds according to the present invention are those compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a salt thereof, wherein _R represents,

Cycloalkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

A heterocyclic group containing at least one nitrogen atom;

基团，R₅代表H、C₁-C₆烷基或芳基，X代表C(Z)₂，Y代表C(Z)₂或单键，Z独立代表H或C₁-C₆烷基。Containing at least one heteroatom selected from S or O and a heterocyclic group substituted by one or more basic groups such as amino, amidino and/or guanidino; R ₂ represents H, C ₁ -C ₃ alkyl, Amino, halogen or hydroxyl, R ₃ represents COOR ₅ , R ₄ represents

Group, R ₅ represents H, C ₁ -C ₆ alkyl or aryl, X represents C(Z) ₂ , Y represents C(Z) ₂ or a single bond, Z independently represents H or C ₁ -C ₆ alkyl .

More preferred compounds according to the present invention are those compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a salt thereof, wherein _R represents,

Cycloalkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

A heterocyclic group containing at least one nitrogen atom; R ₂ represents H, F, C ₁ alkyl, R ₃ represents COOR ₅ , R ₄ represents Group, R ₅ represents H, C ₁ -C ₆ alkyl or aryl, R ₆ represents C ₁ -C ₆ alkyl, aryl, cycloalkyl, heterocyclyl or optionally N-substituted H ₂ NC (Z)-CONH-C(Z)-or H ₂ NC(Z)-group, X represents C(Z) ₂ , Y represents O or C(Z) ₂ , Z independently represents H or C ₁ -C ₆ alkyl.

Other more preferred compounds according to the present invention are those compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a salt thereof, wherein _R represents,

Cycloalkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

基团，R₅代表H、C₁-C₆烷基或芳基，R₇代表H或C₁-C₆烷基，X代表C(Z)₂，Y代表C(Z)₂或单键，Z独立代表H或C₁-C₆烷基。A heterocyclic group containing at least one nitrogen atom; R ₂ represents H, F, C ₁ alkyl, R ₃ represents COOR ₅ , R ₄ represents

Group, R ₅ represents H, C ₁ -C ₆ alkyl or aryl, R ₇ represents H or C ₁ -C ₆ alkyl, X represents C(Z) ₂ , Y represents C(Z) ₂ or a single bond , Z independently represents H or C ₁ -C ₆ alkyl.

Other more preferred compounds according to the present invention are those compounds of formula I, or a pharmaceutically acceptable salt or solvate thereof, or a solvate of a salt thereof, wherein _R represents,

Cycloalkyl substituted by one or more basic groups such as amino, amidino and/or guanidino;

基团，R₅代表H、C₁-C₆烷基或芳基，X代表C(Z)₂，Y代表C(Z)₂或单键，Z独立代表H或C₁-C₆烷基。A heterocyclic group containing at least one nitrogen atom; R ₂ represents H, F, C ₁ alkyl, R ₃ represents COOR ₅ , R ₄ represents

Group, R ₅ represents H, C ₁ -C ₆ alkyl or aryl, X represents C(Z) ₂ , Y represents C(Z) ₂ or a single bond, Z independently represents H or C ₁ -C ₆ alkyl .

The most preferred compounds according to the present invention are those _compounds of formula I or a pharmaceutically acceptable salt or solvate or a solvate of a salt thereof, wherein _R represents pyridyl or piperidyl, R represents H, R ₃ stands for COOR ₅ , R ₄ stands for R ₅ represents H, R ₆ represents C ₁ -C ₆ alkyl or an optionally N-substituted H ₂ NC(Z)-CONH-C(Z)- or H ₂ NC(Z)-group, X represents CHZ, Y represents CHZ, and Z independently represents H or C ₁ -C ₆ alkyl.

Other most preferred compounds according to the present invention are those compounds of formula I or a pharmaceutically acceptable salt or solvate or a solvate of a salt thereof, wherein _R represents pyridyl or piperidyl, R represents _H , R ₃ stands for COOR ₅ , R ₄ stands for Group, R ₅ represents H, R ₇ represents H, X represents CHZ, Y represents CHZ or a single bond, Z independently represents H or C ₁ -C ₆ alkyl.

基团，R₅代表H，X代表CHZ，Y代表CHZ或单键，Z独立代表H或C₁-C₆烷基。Other most preferred compounds according to the present invention are those compounds of formula I or a pharmaceutically acceptable salt or solvate or a solvate of a salt thereof, wherein _R represents pyridyl or piperidyl, R represents _H , R ₃ stands for COOR ₅ , R ₄ stands for

Group, R ₅ represents H, X represents CHZ, Y represents CHZ or a single bond, Z independently represents H or C ₁ -C ₆ alkyl.

The following definitions will be used throughout this specification and the appended claims:

The term "basic group" denotes a basic group wherein the conjugate acid of the basic group has a pKa of from about -5 to about 25, preferably from 1 to 15.

The term "isostere of a carboxylic acid" denotes an acidic group having a pKa of from about -5 to about 25, preferably from 1 to 15.

The term "C ₁ -C ₆ alkyl" means a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl group having 1 to 6 carbon atoms in the chain, wherein said alkyl group can be any are interrupted by one or more heteroatoms selected from O, N or S. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, vinyl, ethynyl, n-propyl, i-propyl, propenyl, i-propenyl, propynyl, n-butyl , iso-butyl, sec-butyl, tert-butyl, butenyl, iso-butenyl, butynyl and straight and branched pentyl and hexyl.

The term "C ₁ -C ₃ alkyl" means a linear or branched, saturated or unsaturated, substituted or unsubstituted alkyl group having 1 to 3 carbon atoms in the chain, wherein said alkyl group can be any are interrupted by one or more heteroatoms selected from O, N or S. Examples of such alkyl groups include, but are not limited to, methyl, ethyl, vinyl, ethynyl, n-propyl, i-propyl, propenyl, i-propenyl, propynyl.

The term "C ₁ alkyl" means a substituted or unsubstituted alkyl group having 1 carbon atom. Examples of the alkyl group include, but are not limited to, methyl.

The term "C ₁ -C ₆ alkoxy" denotes an alkyl-O- group, wherein C ₁ -C ₆ alkyl is as defined above.

The term "C ₁ -C ₃ alkoxy" denotes an alkyl-O- group, wherein C ₁ -C ₃ alkyl is as defined above.

The term "heterocyclyl" denotes a substituted or unsubstituted, 4- to 10-membered monocyclic or polycyclic ring system, wherein one or more atoms in the monocyclic or polycyclic ring is an element other than carbon, such as nitrogen, Oxygen or sulfur, especially 4-, 5- or 6-membered aromatic or aliphatic heterocyclic groups, including (but not limited to) azetidine, furan, thiophene, pyrrole, pyrroline, pyrrolidine , dioxolane, oxathiolane, oxazolane, oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazole, pyrazoline, pyrazolidine, isoxane Azole, isothiazole, oxadiazole, furoxan, triazole, thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane, oxathione, thiomorpholine, Pyridazine, pyrimidine, pyrazine, piperazine, triazine, thiadiazine, dithiazine, azaindole, azaindoline, indole, indoline, 1,5-naphthyridine radicals and are understood to include all isomers of the radicals defined above. The term "azetidinyl", for example, should be understood to include the 2- and 3-isomers and the terms "pyridyl" and "piperidinyl", for example, should be understood to include the 2-, 3- and 4-isomers .

The term "cycloalkyl" means a saturated or unsaturated, substituted or unsubstituted, non-aromatic, ring consisting of 3, 4, 5, 6 or 7 carbon atoms, including but not limited to cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl, Cycloheptyl, Cyclobutenyl, Cyclopentenyl, Cyclohexenyl, Cycloheptenyl, Cyclopentadienyl, Cyclohexadienyl and Cycloheptyl Alkenyl.

The term "halogen" includes fluoro, chloro, bromo and iodo groups.

The term "aryl" denotes a substituted or unsubstituted _C6 - _C14 aromatic hydrocarbon and includes, but is not limited to, phenyl, naphthyl, indenyl, antracenyl, fenantrenyl, and fluorenyl.

The term "aryloxy" means an aryl-O- group in which aryl is as defined above.

The term "acyl" denotes an alkyl-CO- group in which alkyl is as defined above.

The term "aroyl" means an aryl-CO- group in which aryl is as defined above.

The term "alkylthio" means an alkyl-S- group in which alkyl is as defined above.

The term "arylthio" means an aryl-S- group in which aryl is as defined above.

The term "aroylamino" denotes an aroyl-N(Z)- group wherein aroyl and Z are as defined above.

The term "acylamino" means an acyl-N(Z)- group wherein acyl and Z are as defined above.

The term "carbamoyl" denotes a _H2N -CO- group.

The term "alkylcarbamoyl" denotes a _Z2N -CO- group, wherein Z is as defined above.

The term "substituted" means "C ₁ alkyl", "C ₁ -C ₃ alkyl", "C ₁ -C ₆ alkyl", "cycloalkyl", "heterocyclyl", "Aryl", _H2NC (Z)-CONH-C(Z)- or _H2NC (Z)-groups, each substituted by one or more of the following groups: acyl, amido, alkyl, alkane Carbamoyl, alkylthio, alkoxy, aroyl, aroylamino, aryloxy, arylthio, amidino, amino, aryl, carbamoyl, carboxyl, cyano, cycloalkyl, methyl Acyl, guanidino, halogen, heterocyclic, hydroxyl, oxo, nitro, thiol, thio, Z ₂ N-CO-O-, ZO-CO-NZ- or Z ₂ N-CO-NZ- group.

The pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are included within the scope of the present invention. It is also understood that all possible diastereoisomeric forms are included within the scope of the invention. The present invention also includes derivatives of compounds of formula I, which are compounds of formula I having physiological functions such as prodrugs.

Depending on the reaction conditions, the compounds of formula I can be obtained in neutral or salt form or as solvates such as hydrates, and all are included within the scope of the present invention. preparation

The present invention also provides the preparation methods A-C of the compound of general formula I. Method A

Preparation method A of the compound of general formula I, wherein R ₁ , R ₅ , R ₆ and Z are as defined above and R ₂ is H, R ₃ is COOR ₅ , R ₄ represents Group, X is C(Z) ₂ , Y is C(Z) ₂ , the method comprises the following steps:

a) compounds of general formula II

R ₁ -X-OH (II) wherein R ₁ and Z are as defined for formula I and X is C(Z) ₂ , which is commercially available or obtained by known techniques, under standard conditions with suitable reagents such as PPh ₃ /CBr ₄ , TosCl/pyridine or (CF ₃ SO ₂ ) ₂ O/TEA, can be converted into the compound of general formula III,

R ₁ -XL (III) wherein L is a suitable leaving group such as chlorine, bromine, iodine, triflate or tosyl.

b) thereafter, the compound of general formula III can be combined with the compound of general formula IV, Compounds of general formula IV can be purchased or obtained by known techniques, and react under standard conditions to obtain compounds of general formula V in the presence of a suitable base such as K ₂ CO ₃ or NaH,

c) Thereafter, compounds of general formula V can be converted to compounds of general formula VI by treatment with formaldehyde in the presence of a suitable base such as _Et2NH under standard conditions

在合适的碱如LDA或NaH存在下、在标准条件下，用通式III的烷基化剂处理，However, if Y is CH(Z), compounds of general formula VI can be prepared by combining a compound of general formula VII,

Treatment with an alkylating agent of general formula III under standard conditions in the presence of a suitable base such as LDA or NaH,

R ₁ -XL (III) wherein R ₁ is as defined in formula I and L is a suitable leaving group such as chlorine, bromine, iodine, triflate or tosyl, yields compounds of general formula VIII,

Thereafter, compounds of general formula VIII can be reacted with the appropriate aldehyde CHO(Z), wherein Z is as defined for formula I, in the presence of a suitable base such as KOtBu, LDA or NaH under standard conditions to give compounds of general formula VI compound.

d) the compound of general formula VI can be further combined with the compound of general formula IX

基团，X是C(Z)₂和Y是C(Z)₂。方法BR ₆ PO ₂ H ₂ (IX) wherein R ₆ is as defined for formula I, reacts under standard conditions in the presence of a suitable reagent such as BSA or HMDS to give a compound of general formula I, wherein R ₁ , R ₅ , R ₆ and Z are as defined above, R ₂ is H, R ₃ is COOR ₅ , R ₄ represents

group, X is C(Z) ₂ and Y is C(Z) ₂ . Method B

基团，该方法包括以下步骤：Preparation method B of the compound of general formula I, wherein R ₁ , R ₂ , R ₅ , R ₆ and Z are as defined above, R ₃ is COOR ₅ , X is C(Z) ₂ , Y is O, and R ₄ represents

group, the method includes the following steps:

a) make the compound of general formula X

R ₁ -XCO-R ₂ (X) wherein R ₁ , R ₂ and Z are as defined in formula I and X is C(Z) ₂ , in the presence of a suitable reagent such as TMSCN/ZnI ₂ or KCN/HOAc, Reaction under standard conditions, obtains the compound of general formula XI, wherein R ₁ and R ₂ are as defined in formula I and X is C(Z) ₂ .

b) Thereafter, compounds of general formula XI can be treated with suitable reagents such as HCl or HCl/MeOH under standard conditions to give compounds of general formula XII, wherein R ₁ and R ₂ are as defined in formula I and X is C(Z) ₂ .

c) Thereafter, the compound of general formula XII can be combined with the compound of general formula XIII

基团，X是C(Z)₂和Y是O。方法CR ₆ PO ₃ H ₂ (XIII) wherein R ₆ is as defined in general formula I, which is commercially available, well known in the literature, or obtained by known techniques, in a suitable coupling reagent such as DCC/DMAP, PyBop/ In the presence of DIPEA or SOCl ₂ , react under standard conditions to obtain compounds of general formula I, wherein R ₁ , R ₂ , R ₅ , R ₆ and Z are as defined above, R ₃ is COOR ₅ , and R ₄ represents

group, X is C(Z) ₂ and Y is O. Method C

The preparation method C of the compound of general formula I, wherein R ₁ and R ₂ are as defined above, X and Y are C(Z) ₂ or a single bond, R ₃ and R ₄ are COOR ₅ , the method comprises the following steps: a) making Compounds of general formula XIV wherein R _{and R} are as defined in formula I and Y is C(Z) or _a single bond, which is commercially available, well known in the literature or obtained using known techniques, and a compound of general formula III,

R ₁ -XL (III) wherein R ₁ is as defined in formula I, X is C(Z) ₂ and L is a suitable leaving group such as Cl, Br, I or tosyl, in a suitable base such as Under the presence of LDA or NaH, react under standard conditions, obtain the compound of general formula XV,

b) Hydrolysis of compounds of general formula XV, for example by treatment with aqueous NaOH or aqueous TFA under standard conditions, affords compounds of general formula I in which R _{and R} are as defined above and X and Y are C(Z ₎ or a single bond, _R3 and _R4 are COOH. Method D

基团，该方法包括以下步骤：The preparation method D of the compound of general formula I, wherein R ₁ , R ₂ , R ₅ , R ₇ , X, Y and Z are as defined above, R ₃ is COOR ₅ and R ₄ represents

group, the method includes the following steps:

a) compounds of general formula XV Can be with the compound of general formula XVI,

HR ₇ NOH (XVI) wherein R ₇ is as defined in formula I, reacted under standard conditions in the presence of a suitable reagent such as DCC/DMAP to give a compound of general formula I, wherein R ₁ , R ₂ , R ₅ , R ₇ , X, Y and Z are as defined above, R ₃ is COOR ₅ and R ₄ represents group.

Those skilled in the art can understand that in the above-mentioned methods, the functional groups of the intermediate compounds may need to be protected by protecting groups.

Functional groups that require protection include hydroxyl, amino, mercapto and carboxylic acid. Suitable protecting groups for hydroxy groups include trialkylsilyl or diarylalkylsilyl groups such as tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl silyl), tetrahydropyranyl and benzyl. Suitable protecting groups for amino, amidino and guanidino include t-butyloxycarbonyl and benzyloxycarbonyl. Suitable protecting groups for mercapto include CO-C _1-6 alkyl, p-methoxybenzyl and trityl _. Suitable protecting groups for carboxylic acids include C _1-6 alkyl and benzyl esters.

Protecting groups can be removed according to techniques well known to those skilled in the art and as described below.

Certain protected derivatives of compounds of formula I, which may be prepared prior to the final deprotection stage in order to form compounds of formula I, are novel compounds.

The use of protecting groups is described in "Protecting Groups in Organic Synthesis", 2nd Ed., T.W. Greene & P.G.M. Wutz, Wiley-Interscience (1991). The protecting group can also be a polymeric resin such as Wang resin or 2-chlorotrityl chloride resin.

Those skilled in the art will understand that although these protected derivatives of the compound of formula I may not have pharmacological activity themselves, they will be metabolized in vivo to form the pharmacologically active compound of the present invention after parenteral or oral administration. Therefore, these derivatives are called "prodrugs". All prodrugs of the compounds of formula I are included within the scope of this invention.

It should also be recognized that all polymorphs, amorphous forms, anhydrates, hydrates, solvates of the compounds of the present invention are within the scope of the present invention. pharmaceutical preparations

In another aspect, the present invention relates to pharmaceutical compositions comprising as active ingredient at least one compound of the present invention or a pharmaceutically acceptable salt thereof.

For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other routes of administration. The pharmaceutical formulations comprise a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent or a capsule. These pharmaceutical formulations are another object of the invention. Usually the amount of active compound is between 0.1-95% by weight of the preparation.

In the preparation of pharmaceutical formulations containing the compounds of the present invention, the selected compound may be mixed with solid, powdered ingredients such as lactose, sucrose, sorbitol, mannitol, starch, pullulan, cellulose derivatives, gelatin or other The appropriate ingredients are mixed and blended with disintegrants and lubricants such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture can then be processed into granules or compressed into tablets.

Soft gelatin capsules may be prepared from capsules containing the active compound or mixture of active compounds of the invention, vegetable oil, fat or other suitable carrier for soft gelatin capsules. Hard gelatine capsules may contain granules of the active compound. Hard gelatine capsules may also contain the active compound in admixture with solid powdered ingredients such as lactose, sucrose, sorbitol, mannitol, potato starch, corn starch, pullulan, cellulose derivatives or gelatin.

Dosage units for rectal administration may be formulated as (i) suppositories containing the active substance in admixture with a neutral fatty base; (ii) containing the active substance in admixture with vegetable oil, paraffin oil or other suitable carriers for gelatin rectal capsules. (iii) in the form of pre-made micro-enemas; or (iv) in the form of dry micro-enema formulations to be reconstituted in a suitable solvent prior to administration.

Liquid preparations may be prepared in the form of syrups or suspensions, for example, solutions or suspensions containing the active ingredient and the balance comprising, for example, a mixture of sugar or sugar alcohol and ethanol, water, glycerol, propylene glycol and polyethylene glycol. These liquid preparations may contain coloring agents, flavoring agents, preservatives, saccharine and carboxymethylcellulose or other thickening agents, if desired. Liquid preparations can also be prepared in dry powder form for reconstitution with a suitable solvent before use.

Solutions for parenteral administration can be prepared as solutions of the compounds of the present invention in pharmaceutically acceptable solvents. These solutions also contain stabilizers and/or buffers. Solutions for parenteral administration can also be prepared as a dry preparation for reconstitution with a suitable solvent before use.

The usual daily dosage of active substances varies within wide ranges and will depend on many factors such as the individual requirements of each patient, the route of administration and the disease to be treated. In general, oral and parenteral dosages should be in the range of 0.1-1000 mg of active substance per day. Medical and Pharmaceutical Uses

The compounds of the invention are inhibitors of carboxypeptidase U per se or after administration as prodrugs. Accordingly, the compounds of the present invention are expected to be useful in diseases in which inhibition of carboxypeptidase U is beneficial, such as the treatment or prevention of thrombosis and hypercoagulability in blood and tissues of mammals, including humans.

Hypercoagulability is known to lead to thromboembolic disease. Symptoms that may be mentioned in connection with hypercoagulability and thromboembolic diseases include protein C resistance and inherited or acquired deficiencies in antithrombin III, protein C, protein S and heparin cofactor II. Other symptoms known to be associated with hypercoagulability and thromboembolic disease include circulatory and septic shock, circulating antiphospholipid antibodies, homocysteinami, heparin-induced thrombocytopenia, and fibrinolysis defect. The compounds of the invention are therefore suitable for the treatment and/or prophylaxis of these diseases. The compounds of the invention are also useful in the treatment of diseases in which there is an undesirable excess of pro CPU/CPU.

Specific conditions that may be mentioned include the treatment and/or prophylaxis of venous thrombosis and pulmonary embolism, arterial thrombosis (eg in myocardial infarction, unstable angina, thrombosis-based stroke and peripheral arterial thrombosis) and often in arterial fibrosis Systemic embolism from the anterior chamber during fibrillation or from the left ventricle after transmural myocardial infarction.

In addition, the compounds of the present invention are expected to be effective in preventing reocclusion and restenosis (i.e., thrombosis) after thrombolysis, percutaneous transluminal angioplasty (PTA) and coronary artery bypass surgery; in the prevention of microsurgery and vascular Effective in rethrombosis after general surgery.

Other indications include treatment and/or prophylaxis of disseminated intravascular coagulation caused by bacteria, complex trauma, poisoning, or any other mechanism when blood is in contact with foreign body surfaces in the body such as vascular grafts, vascular stents, vascular catheters , fibrinolytic therapy when mechanical and biological prosthetic valves or any other medical device comes into contact, and fibrin when blood comes into contact with medical devices outside the body such as during cardiovascular surgery using an artificial heart-lung machine or during hemodialysis Dissolving treatment.

The compounds of the present invention can also be combined with any antithrombotic drugs with different mechanisms of action, such as antiplatelet drugs aspirin, ticlopidine, clopidogrel, thromboxane receptor and/or synthetase inhibitors, fibrin Proreceptor antagonists, prostacyclin mimetics and phosphodiesterase inhibitors and ADP-receptor ( _P2T ) antagonists and thrombin inhibitors are combined and/or co-administered.

The compounds of the present invention can also be combined with thrombolytic agents such as tissue plasminogen activator (natural, recombinant or modified), streptokinase, urokinase, prourokinase, methoxybenzoyl plasminogen-streptokinase activator Compound (APSAC), animal salivary gland plasminogen activator, etc., combined and/or co-administered in thrombotic diseases, especially in the treatment of myocardial infarction and shock. in vitro test

Inhibitory effect of compounds of the present invention using Dirk Hendriks, Simon Scharpé and Marc van Sande, Clinical Chemistry, 31, 1936-1939 (1985); and Wei Wang, Dirk F. Hendriks, Simon S. Scharpé, The Journal of Biological Chemistry, 269 , 15937-15944 (1994) described the evaluation of the assay method.

Embodiment General experimental method

Mass spectra were recorded on a Finnigan MAT TSQ 700 triple quadrupole mass spectrometer (FAB-MS) equipped with an electrospray interface and a VG Platform II mass spectrometer equipped with an electrospray interface (LC-MS). ¹ H NMR and ¹³ C NMR measurements were performed on a Varian UNITY plus 400, 500 and 600 spectrometer operating at ¹ H frequencies of 400, 500 and 600 MHz, respectively. Chemical shifts are expressed in ppm using the solvent as an internal standard. The organic extract was dried with MgSO ₄ or Na ₂ SO ₄ as desiccant. Chromatographic separation was performed with Merck silica gel 60 (0.063-0.200 mm). HPLC separation was performed on a HIGHCROM KR100-10C8 column.

Example 15-Amino-2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonooxy]-pentanoic acid (a) 5-tert-butoxycarbonylamino- 2-Hydroxy-pentanoic acid

Di-tert-butyl dicarbonate (30.8 g, 0.141 mol) was added in batches to 5-amino-2-hydroxy-pentanoic acid (17.0 g, 0.128 mol) in 0.5M NaOH (240 mL) at 5 °C over 5 minutes and dioxane (240mL) solution. The mixture was stirred at room temperature for 2.5 hours. During this time 0.5M NaOH was added to maintain pH 9-10. Dioxane was removed under reduced pressure and the aqueous phase was washed with ether. The aqueous layer was acidified to pH 2-3 with KHSO ₄ and extracted with ethyl acetate (3×300 mL). The combined organic phases were washed with water and brine, dried and concentrated under reduced pressure to give crude 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid (22.0 g, 73.7%). (b) 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester

A solution of methyl iodide (11.5 mL, 0.189 mol) in DMF (50 mL) was added dropwise to 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid (22.0 g, 94.4 mmol) and NaHCO ₃ ( 11.8 g, 141 mmol) in DMF (150 mL). After stirring overnight, water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried and concentrated under reduced pressure. The crude product was purified by chromatography (heptane/ethyl acetate, 1:1) to give methyl 5-tert-butoxycarbonylamino-2-hydroxy-pentanoate (9.9 g, 42.5%). (c) 2-[(1-Benzyloxycarbonylamino-2-methyl-propyl)-methoxy-phosphonooxy]-5-tert-butoxycarbonylamino-pentanoic acid methyl ester

A solution of PyBOP (2.1 g, 4.0 mmol) in DMF (3 mL) was added to (1-benzyloxycarbonylamino-2-methyl-propyl)-phosphonic acid monomethyl ester (1.0 g, 3.32mmol) and methyl 5-tert-butoxycarbonylamino-2-hydroxy-pentanoate (865mg, 3.5mmol) in DMF (4mL). DIPEA (2.28 mL, 13.3 mmol) was added dropwise and the mixture was stirred overnight. Ethyl acetate was added and the mixture was washed with 10% _KHSO4 , saturated _NaHCO3 and brine and dried. Concentration under reduced pressure followed by chromatography (heptane/EtOAc, 1:1→1:6) gave 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-methoxy -Phosphonooxy]-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (1.21 g, 69%). (d) 2-[(1-Benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonooxy]-5-tert-butoxycarbonylamino-pentanoic acid

Add 1M LiOH (5 mL) to 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-methoxy-phosphonooxy]-5-tert-butoxycarbonylamino-pentane A solution of methyl ester (187 mg, 0.35 mmol) in acetonitrile (5 mL). The mixture was stirred overnight at 50 °C and concentrated under reduced pressure. The crude product was purified by chromatography (iPrOH/conc. _NH3water / _H2O , 4:2:1) to afford 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy -Phosphonooxy]-5-tert-butoxycarbonylamino-pentanoic acid (180 mg, 100%). (e) 5-Amino-2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonooxy]-pentanoic acid

TFA (3 mL) was added to 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonooxy]-5-tert-butoxycarbonylamino-pentanoic acid (150 mg , 0.3mmol) in dichloromethane/acetonitrile (1:1, 15mL) solution. The solution was stirred for 120 min and concentrated under reduced pressure to afford the title compound as TFA salt (174 mg, 100%). ¹ H NMR (500MHz, CD ₃ OD): δ1.02(t, 6H), 1.66-2.0(m, 4H), 2.23(m, 1H), 2.93(m, 2H), 3.91(m, 1H), 4.85 (bs, 1H), 5.12 (m, 2H), 7.28-7.42 (m, 5H). MS(+)403.3(M+1)

Example 22-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxyl-phosphonooxy]-5-guanidino-valeric acid (a)2-[(1-benzyloxy Carbonylamino-2-methyl-propyl)-hydroxy-phosphonooxy]-5-guanidino-pentanoic acid

A solution of S-methylisothiourea hydrogensulfate (25 mg, 90 μmol) in 1M NaOH (0.18 mL) was added to 5-amino-2-[(1-benzyloxycarbonylamino-2-methyl-propyl) -Hydroxy-phosphonooxy]-pentanoic acid (36 mg, 90 μmol) and 1M NaOH (0.18 mL) in water/MeOH (1:1, 0.4 mL). The reaction mixture was stirred at 50 °C for 6 hours and concentrated under reduced pressure. The crude product was purified by HPLC (0-50% acetonitrile, 0.1% TFA in water) to give the title compound as TFA salt (19 mg, 38%) ¹ H NMR (500 MHz, CD ₃ OD): δ 1.02 (t, 6H ), 1.60-1.98(m, 4H), 2.23(m, 1H), 3.20(m, 2H), 3.91(m, 1H), 4.82(bs, 1H), 5.11(m, 2H), 7.26-7.42( m, 5H). MS (+) 445 (M+1).

Example 35-Amino-2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy}-pentanoic acid (a) 2-{[1-(2-Benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy}-5-tert-butyl Oxycarbonylamino-valeric acid methyl ester

Thionyl chloride (49 μL, 0.67 mmol) was added dropwise to [1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propanylamino at -20°C under argon atmosphere ]-valeric acid (208mg, 0.48mmol) in DMF (5mL). The mixture was stirred at -5°C for 35 minutes. A solution of methyl 5-tert-butoxycarbonylamino-2-hydroxy-pentanoate (166 mg, 0.67 mmol) in DMF (1 mL) was added and the mixture was stirred at room temperature for 90 minutes. Ethyl acetate was added and the mixture was washed with 1M HCl, dried and concentrated under reduced pressure. The crude product was purified by chromatography ( _CHCl3 /MeOH/ _H2O , 10:1:0→10:5:1) to give 2-{[1-(2-benzyloxycarbonylamino-3-benzene (2-methyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy}-5-tert-butoxycarbonylamino-pentanoic acid methyl ester (211 mg, 66%). (b) 2-{[1-(2-Benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy}-5-tert-butyl Oxycarbonylamino-valeric acid

Add 1M LiOH (3.5 mL) to 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy} -5-tert-butoxycarbonylamino-pentanoic acid methyl ester (211 mg, 0.32 mmol) in acetonitrile (3.5 mL) and the mixture was stirred for 3 hours. Ethyl acetate was added and the mixture was washed with 1M HCl, dried and concentrated to give crude 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl ]-Hydroxy-phosphonooxy}-5-tert-butoxycarbonylamino-valeric acid (208 mg, 100%). (c) 5-amino-2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxyl-phosphonooxy}-pentane acid

TFA (5 mL) was added to 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy}-5 - tert-butoxycarbonylamino-valeric acid (208 mg, 0.32 mmol) in acetonitrile (5 mL) and the mixture was stirred for 90 minutes. The reaction mixture was concentrated under reduced pressure to afford the crude title compound as TFA salt (212 mg, 100%). The crude title compound, 20 mg, was purified by chromatography (iPrOH/conc. _NH3water / _H2O , 4:2:1) to afford the title compound as its TFA salt (19 mg, 94%). ¹ H NMR (500MHz, CD ₃ OD): δ0.85-0.95(m, 6H), 1.70-2.0(m, 4H), 2.05-2.13(m, 1H), 2.85-3.05(m, 2H), 3.05 -3.12 (m, 1H), 4.10 (bs, 1H), 4.55 (m, 1H), 4.90 (m, 1H), 5.09 (s, 2H), 7.20-7.35 (m, 10H).

Example 42-{[1-(2-Benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxyl-phosphonooxy}-5-guanidino-pentyl Acid (a) 5-Amino-2-hydroxy-pentanoic acid methyl ester

TFA (2 mL) was added to a solution of 5-tert-butoxycarbonylamino-2-hydroxy-pentanoic acid methyl ester in dichloromethane (10 mL) and the mixture was stirred for 3 hours, then concentrated under reduced pressure to give Crude methyl 5-amino-2-hydroxy-pentanoate (1 g). (b) 5-(guanidino-ω,ω'-bis(tert-butoxycarbonyl)-2-hydroxy-pentanoic acid methyl ester

To a solution of 5-amino-2-hydroxy-pentanoic acid methyl ester (0.5 g, 2.0 mmol) in acetonitrile (5 mL) was added tert-butoxycarbonylimino-pyrazol-1-yl-methyl)-carbamic acid tert-Butyl ester (0.77 g, 2.5 mmol) followed by DIPEA (0.86 mL, 5 mmol). After stirring for 60 minutes, ethyl acetate was added. The mixture was washed with 1M HCl, saturated NaHCO ₃ and brine, dried and concentrated under reduced pressure. The crude product was purified by chromatography (heptane/ethyl acetate, 1:0 → 1:3) to give 5-(guanidino-ω,ω'-bis(tert-butoxycarbonyl)-2-hydroxy - Methyl valerate (0.27 g, 35%). (c) 2-{[1-(2-Benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]- Hydroxy-phosphonooxy}-5-[guanidino-ω,ω'-bis(tert-butoxycarbonyl)]-pentanoic acid methyl ester

Thionyl chloride (70 μL, 0.97 mmol) was added dropwise to [1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propanylamino at -20°C under argon atmosphere ]-phosphonic acid (301 mg, 0.69 mmol) in DMF (5 mL). The mixture was stirred at -5°C for 20 minutes. A solution of 5-(guanidino-ω,ω'-bis(tert-butoxycarbonyl)-2-hydroxy-pentanoic acid methyl ester (270 mg, 0.69 mmol) in DMF (1 mL) was added and the mixture was stirred at room temperature for 180 Min. Ethyl acetate was added and the mixture was washed with 1M HCl, dried and concentrated under reduced pressure. The crude product was purified by chromatography (toluene/ethyl acetate, 1:1 → 0:1) to give 2-{ [1-(2-Benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy}-5-[guanidino-ω,ω'- Bis(tert-butoxycarbonyl)]-pentanoic acid methyl ester (0.27 g, 48%). (d) 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino) -2-Methyl-propyl]-hydroxy-phosphonooxy}-5-[guanidino-ω,ω'-bis(tert-butoxycarbonyl)]-pentanoic acid

A solution of LiOH (42 mg, 1.0 mmol) in water (1.0 mL) was added to 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl] -Hydroxy-phosphonooxy}-5-[guanidino-ω,ω'-bis(tert-butoxycarbonyl)]-pentanoic acid methyl ester (160 mg, 0.2 mmol) in acetonitrile (1.0 mL) The mixture was stirred for 15 minutes. Ethyl acetate was added and the mixture was washed with 1M HCl and brine, dried and concentrated to give crude 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl- Propyl]-hydroxy-phosphonooxy}-5-[guanidino-ω,ω'-bis(tert-butoxycarbonyl)]-pentanoic acid (160 mg, 100%). (e) 2-{[1-(2-Benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy}-5-guanidino- Valeric acid

TFA (2 mL) was added to 2-{[1-(2-benzyloxycarbonylamino-3-phenyl-propionylamino)-2-methyl-propyl]-hydroxy-phosphonooxy}-5 -[Guidino-ω,ω'-bis(tert-butoxycarbonyl)]-pentanoic acid (160 mg, 0.2 mmol) in acetonitrile (5 mL) and the mixture was stirred for 60 minutes, then concentrated under reduced pressure . The crude product was purified by chromatography (iPrOH/conc. _NH3water / _H2O , 4:2:1) to afford the title compound as TFA salt (30 mg, 21%). ¹ H NMR (500MHz, CD ₃ OD): δ0.80-0.98(m, 6H), 1.53-1.95(m, 4H), 2.01-2.30(m, 1H), 2.90(m, 1H), 3.10-3.30 (m, 3H), 3.94-4.10 (m, 1H), 4.41-4.55 (m, 1H), 4.68 (m, 1H), 5.03 (m, 2H), 7.18-7.37 (m, 5H). MS (+) 592 (M+1).

Example 52-Hydroxycarbamoyl-4-piperidin-4-yl-butyric acid (a) piperidin-4-yl-acetic acid

Pyridin-4-yl-acetic acid hydrochloride (20.0 g, 115 mmol) was added to a water/25% ammonia (125 mL:10 mL) solution. The mixture was degassed and flushed with nitrogen, then rhodium on activated alumina (0.45 g) was added. The mixture was degassed again and then stirred under a hydrogen pressure of 50 bar for 16 hours. The reaction mixture was filtered through filter paper to obtain most of the catalyst, which was washed with methanol before recycling. The filtrate was then filtered through celite and concentrated to give a white solid (19.7 g, 96% yield). (b) tert-butyl 4-carboxymethyl-piperidine-1-carboxylate

To a solution of piperidin-4-yl-acetic acid (19.7 g, 148 mmol) in THF-water (417 mL, 1:1) was added di-tert-butyl dicarbonate (32.3 g, 148 mmol) and sodium bicarbonate (12.5 g, 148 mmol), and the reaction was stirred at room temperature for 16 hours. Then THF was removed under reduced pressure and the aqueous phase was extracted with dichloromethane, the organic layer was discarded. The aqueous layer was then acidified to pH 1-2 with 1M HCl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried and concentrated under reduced pressure to give tert-butyl 4-carboxymethyl-piperidine-1-carboxylate (16.7 g, 46%). (c) tert-butyl 4-(2-hydroxy-ethyl)-piperidine-1-carboxylate

To a solution of tert-butyl 4-carboxymethyl-piperidine-1-carboxylate (16.7 g, 69.0 mmol) in THF (100 mL) was added diborane (151 mL, 1.0 M THF solution). Hydrogen evolution was rapid and after gas evolution ceased, the reaction was stirred at room temperature for 1 hour. The reaction mixture was recooled to 0 °C and 1M aqueous HCl was added dropwise to the reaction mixture with further evolution of hydrogen gas. Addition of HCl was continued until hydrogen evolution almost ceased. The mixture was then stirred for 10 minutes and made basic (pH 13-14) by adding 1M NaOH solution. The aqueous solution was extracted with ethyl acetate, the organic phase was washed with brine, dried and concentrated under reduced pressure to give tert-butyl 4-(2-hydroxy-ethyl)-piperidine-1-carboxylate (15.2 g, 97%). (d) tert-butyl 4-(2-oxo-ethyl)-piperidine-1-carboxylate

Periodinane (36.1 g, 85.2 mmol) was added to a solution of tert _- butyl 4-(2-hydroxy-ethyl)-piperidine-1-carboxylate (15.0 g, 65.5 mmol) in _CH2Cl2 (230 mL) and stir for 90 minutes. Diethyl ether (560 _mL ) was added and extracted with 10% _Na2S2O3 /saturated _NaHCO3 (1:1, ₃₅₀ mL) to remove the precipitate. The organic layer was washed with 0.5M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure to give tert-butyl 4-(2-oxo-ethyl)-piperidine-1-carboxylate (8.50 g, 57%). (e) 4-[2-(2,2-Dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester

Melconic acid (1.68g, 11.66mmol) and tert-butyl 4-(2-oxo-ethyl)-piperidine-1-carboxylate (2.21g, 9.72mmol) in dichloromethane (40mL ) solution was added acetic acid (0.055 mL, 0.972 mmol) and piperidine (0.096 mL, 0.972 mmol). The mixture was heated at reflux for 3 hours and then allowed to warm to room temperature. After dilution with tert-butyl methyl ether, the mixture was washed with NaHCO ₃ (sat.) and brine. The organic phase was dried, filtered and concentrated. The residue was dissolved in a mixture of EtOH (40 mL) and acetic acid (20 mL). The solution was cooled to 0° C. and NaBH ₄ (0.554 g, 14.6 mmol) was added in portions, then the solution was stirred at room temperature for 30 minutes, then acidified to pH 3 with 1M HCl. The solution was extracted several times with dichloromethane. The combined organic phases were dried, filtered, concentrated and filtered through a pad of silica gel (dichloromethane). Evaporation of the solvent gave 4-[2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-ethyl]-piperidine-1-carboxylic acid tert-Butyl ester as a colorless oil (2.30 g, 65%) which solidified on standing. (f) 2-Hydroxycarbamoyl-4-piperidin-4-yl-butyric acid

4-[2-(2,2-Dimethyl-4,6-dioxo-[1,3]diox Alk-5-yl)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (17.8 mg, 0.05 mmol) and flushed with nitrogen. N,O-bis(trimethylsilyl)-hydroxylamine (0.2 mL) was added by syringe and the resulting solution was stirred at room temperature overnight. The mixture was concentrated under vacuum and the residue was dissolved in dichloromethane/MeOH (4:1) solution and loaded onto a small ion exchange resin plug column (200 mg, isolute ^™ , amino resin) with di It was washed with methyl chloride/MeOH (4:1) and then eluted with dichloromethane/MeOH/AcOH (3:1:1). The eluate was concentrated and the residue was dissolved in dichloromethane/TFA (1:1, 2 mL) solution and stirred at room temperature for 1 hour. Evaporation of the solvent gave the title compound as a TFA salt (16 mg, 93%) as a colorless oil. ¹ H NMR (600MHz, CD ₃ OD): δ1.21-1.40 (m, 4H), 1.53-1.62 (m, 1H), 1.80-1.99 (m, 4H), 2.90-2.98 (m, 2H), 3.06 (t, 1H), 3.32-3.39 (m, 2H). MS(+)231(M+1).

Embodiment 6N-Hydroxy-2-piperidine-3-ylmethyl-propionamic acid (a) 3-hydroxymethyl-piperidine-1-carboxylic acid tert-butyl ester

A solution of 3-hydroxymethyl-piperidine (20.0 g, 0.17 mmol) in acetonitrile was treated with di-tert-butyl dicarbonate (37.9 g, 0.17 mol) and DMAP (2.13 g, 1.74 mmol). The reaction mixture was stirred at room temperature for 5 hours, then concentrated under reduced pressure. The crude product was purified by flash chromatography (Hexane/EtOAc, 70:30) to give tert-butyl 3-hydroxymethyl-piperidine-1-carboxylate (16.0 g, 44%). (b) tert-butyl 3-formyl-piperidine-1-carboxylate

Periodinane (18.2 g, 42.9 mmol) was added to a solution of tert _- butyl 3-hydroxymethyl-piperidine-1-carboxylate (7.10 g, 33.0 mmol) in _CH2Cl2 (230 mL) and stirred for 90 minutes . Diethyl ether (230 mL) was added and extracted with 10% Na ₂ S ₂ O ₃ /saturated NaHCO ₃ (1:1, 230 mL) to remove the precipitate. The organic layer was washed with 0.5M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure to give tert-butyl 3-formyl-piperidine-1-carboxylate (6.50 g, 93%). (c) N-Hydroxy-2-piperidin-3-ylmethyl-propionamic acid

The title compound was prepared by the method described in Example 5 from tert-butyl 3-formyl-piperidine-1-carboxylate. Yield: (50%). ¹ H NMR (600MHz, CD ₃ OD): δ1.18-1.30(m, 1H), 1.61-1.99(m, 6H), 2.64(t, 1H), 2.86(t, 1H), 3.20-3.38(m , 3H). MS(+)217(M+1).

Example 7 2-(6-amino-pyridin-3-ylmethyl)-N-hydroxyl-propionamic acid

The title compound was prepared by the method described in Example 5 from (5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester. Yield: (23%). ¹ H NMR (600MHz, CD ₃ OD): d 2.99-3.10(m, 2H), 3.36-4.01(m, 1H), 6.94(d, 1H), 7.64(s, 1H), 7.82(d, 1H) . MS (+) 226 (M+1).

Example 8 2-(2-Amino-pyridin-4-ylmethyl)-N-hydroxyl-propionamic acid (a)(4-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester

(4-Hydroxymethyl-pyridin-2-yl)-tert-butylcarbamate (1.91 g, 8.51 mmol) was dissolved in dry DMSO (10 mL) and the reaction flask was immersed in a 15 °C water bath. Triethylamine (1.72 g, 17.0 mmol) was added followed by sulfur trioxide pyridine complex (2.41 g, 15.1 mmol). The reaction mixture was stirred for 2 hours and poured onto crushed ice and the product was extracted with _CHCl3 . The organic extract was washed with water, dried and concentrated under reduced pressure. The crude product was purified by flash chromatography (Hexane/EtOAc, 80:20) to afford (4-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.57 g, 83%). (b) 2-(2-Amino-pyridin-4-ylmethyl)-N-hydroxy-propionamic acid

The title compound was prepared by the method described in Example 5 from (4-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester. Yield: (48%). ¹ H NMR (600MHz, CD ₃ OD): δ3.10(dd, 1H), 3.19(dd, 1H), 3.47(dd, 1H), 6.77(d, 1H), 7.82(s, 1H), 7.71( d, 1H). MS (+) 226 (M+1). Example 92-[2-(1-tert-butoxycarbonyl-piperidin-4-yl)-ethyl]-malonic acid

To 4-[2-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-yl)-ethyl]-piperidine-1-carboxylic acid tert- To a solution of the butyl ester (17.8 mg, 0.05 mmol) in acetic acid (1 mL) was added 6M HCl (2 mL). The solution was stirred at room temperature overnight then concentrated to give the title compound as the hydrochloride salt (15 mg, 100%). ¹ H NMR (600MHz, CD ₃ OD): δ1.30-1.40(m, 4H), 1.57-1.64(m, 1H), 1.83-1.90(m, 1H), 1.90-1.98(m, 1H), 3.31 -3.39 (m, 2H). MS(+)216(M+1).

Example 102-[2-(1-tert-butoxycarbonyl-piperidin-3-yl)-methyl]-malonic acid

Using the method described in Example 9, from 3-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-piperidine-1 - tert-butyl carboxylate Preparation of the title compound. Yield: (100%). ¹ H NMR (600MHz, CD ₃ OD): δ1.20-1.30(m, 1H), 1.63-1.76(m, 1H), 1.78-1.97(m, 5H), 2.65(t, 1H), 2.83-2.92 (m, 1H), 3.29-3.38 (m, 2H), 3.42-3.48 (m, 1H). MS(+)202(M+1).

Example 112-[2-(1-tert-butoxycarbonyl-piperidin-4-yl)-methyl]-malonic acid (a) piperidine-1,4-dicarboxylic acid mono-tert-butyl base ester

A solution of piperidine-4-carboxylic acid (24.5 g, 0.19 mmol) in THF/water (1:1, 417 mL) was treated with di-tert-butyl dicarbonate (41.49 g, 0.19 mol) and sodium bicarbonate (16.0 g , 0.19mol) treatment. The reaction mixture was stirred at room temperature for 16 hours. Then THF was removed under reduced pressure and the aqueous phase was washed with dichloromethane. The aqueous layer was then acidified to pH 1-2 with 1M HCl solution and extracted with ethyl acetate. The organic phase was washed with brine and dried to give piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (35.9 g, 83%). (b) 4-Hydroxymethyl-piperidine-1-carboxylic acid-tert-butyl ester

To a solution of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (19.3 g, 84.0 mmol) in THF (100 mL) was added diborane (185 mL, 1.0 M THF solution). Hydrogen evolution was rapid and after gas evolution ceased, the reaction was stirred at room temperature for 1 hour. The reaction mixture was recooled to 0 °C and 1M aqueous HCl was added dropwise to the reaction mixture with further evolution of hydrogen gas. Addition of HCl was continued until hydrogen evolution almost ceased. The mixture was then stirred for 10 minutes and made basic (pH 13-14) by adding 1M NaOH solution. The aqueous solution was extracted with ethyl acetate, the organic phase was washed with brine, dried and concentrated under reduced pressure to give tert-butyl 4-hydroxymethyl-piperidine-1-carboxylate (18.12 g, 100%). (c) tert-butyl 4-formyl-piperidine-1-carboxylate

Periodinane (26.9 g, 63.5 mmol) was added to a solution of tert _- butyl 4-hydroxymethyl-piperidine-1-carboxylate (10.5 g, 48.8 mmol) in _CH2Cl2 (200 mL) and stirred for 90 minutes . Diethyl ether (560 mL) was added and extracted with 10% Na ₂ S ₂ O ₃ /saturated NaHCO ₃ (1:1, 300 mL) to remove the precipitate. The organic layer was washed with 0.5M NaOH solution and brine. The organic phase was dried and concentrated under reduced pressure. Purification by flash chromatography (Hexane/EtOAc, 8:2) gave tert-butyl 4-formyl-piperidine-1-carboxylate (8.5 g, 81%). (d) 2-[2-(1-tert-butoxycarbonyl-piperidin-4-yl)-methyl]-malonic acid

The title compound was prepared by the procedure described in Examples 5 and 9 from tert-butyl 4-formyl-piperidine-1-carboxylate. Yield: (100%). ¹ H NMR (600MHz, CD ₃ OD): δ1.38-1.48 (m, 2H), 1.61-1.75 (m, 1H), 1.82-1.90 (m, 2H), 1.92-2.02 (m, 2H), 2.90 -3.01 (m, 2H), 3.35-3.42 (m, 2H), 3.42-3.48 (m, 1H). MS(+)202(M+1).

Example 12 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid

Using the method described in Example 9, from [5-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridine-2 -yl]-carbamate tert-butyl ester to prepare the title compound. Yield: (100%). ¹ H NMR (600 MHz, CD ₃ OD): δ 3.08 (d, 2H), 3.66 (t, 1H), 6.98 (d, 1H), 7.73 (s, 1H), 7.92 (d, 1H). MS(+)211(M+1).

Example 13 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethyl)-malonic acid

Using the method described in Example 9, from [4-(2,2-dimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridine-2 -yl]-carbamate tert-butyl ester to prepare the title compound. Yield: (100%). ¹ H NMR (600 MHz, CD ₃ OD): δ 3.10 (d, 2H), 3.79 (t, 1H), 6.84 (d, 1H), 7.92 (s, 1H), 7.77 (d, 1H). MS(+)211(M+1).

Example 14 2-(2-Amino-pyridin-4-ylmethyl)-succinic acid (a) 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethylene)-succinic acid 4- Benzyl ester 1-tert-butyl ester

Butyllithium (1.6M in hexane, 14.8ml, 23.7mmol) was added dropwise to 4-benzyl 2-(diethoxy-phosphoryl)-succinate 1- tert-Butyl ester (9.50 g, 23.7 mmol) in THF (75 mL). After stirring at 0 °C for 1 hour, the solution was transferred to a solution of (4-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (3.70 g, 16.6 mmol) in THF (75 mL). The resulting reaction mixture was stirred at 0°C for 1 hour before being warmed to 25°C and the mixture was stirred overnight. Water ( ₄₀₀ mL) was added and the product was extracted with _CH2Cl2 (3 x 50 mL). The combined organic layers were dried and concentrated. Flash chromatography (Hexane/EtOAc, 4:1) afforded 4-benzyl 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethylene)-succinate 1-tert-butyl Base ester 4.30 g (55%). (b) 1-tert-butyl 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethyl)-succinate

2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester (2.81 g, 7.60 mmol) and Pd/C ( 10%, 400 mg) was suspended in EtOH and hydrogenated at 41 atm and 28°C for three days. The catalyst was removed from the reaction mixture by filtration. The catalyst was washed with EtOH (96%). 1M _K2CO3 (30 _mL ) was added to the filtrate followed by water (50 mL). After two days, the reaction mixture was evaporated to about 80 mL, then brine (10 mL) was added and the reaction mixture was extracted with ether. The aqueous phase was acidified to pH=3 and extracted with chloroform. Methanol (25 mL) was added and the reaction mixture was dried (Na ₂ SO ₄ +CaSO ₄ ) and filtered to give 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethyl)-succinic acid 1-tert - Butyl ester (1.90 g, 83%). (c) 2-(2-Amino-pyridin-4-ylmethyl)-succinic acid

To a solution of 1-tert-butyl 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethyl)-succinate (164 mg, 0.43 mmol) in dichloromethane (1.5 mL) was added TFA (1.5 mL). The reaction mixture was stirred for 2.5 hours, then concentrated under reduced pressure. The residue was lyophilized to give the title compound as TFA salt (126 mg, 87%) ¹ H NMR (500 MHz, D ₂ O): δ 2.58-2.80 (m, 2H), 2.88-3.07 (m, 2H), 3.13 -3.26 (m, 1H), 6.79-6.84 (dd, 1H), 6.84-6.88 (s, 1H), 7.69-7.75 (d, 1H). MS (+) 225 (M+1).

Example 15 trans-2-(4-amino-cyclohexylmethyl)-succinic acid (a) 4-[N-(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid

To a solution of cis-4-aminocyclohexanecarboxylic acid (9.90 g, 69.0 mmol) in water (120 mL) and dioxane (120 mL) was added KOH (3.73 g, 56 mmol) followed by di-tert-butyl dicarbonate (15.3 g, 70.0 mmol). The reaction mixture was stirred overnight at room temperature. Water was added and the product was extracted with _CHCl3 . The combined organic extracts were washed with water, dried and concentrated under reduced pressure to give 4-[N-(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (14.1 g, 84%). (b) [4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester

4-[N-(tert-butoxycarbonyl)amino]-cyclohexanecarboxylic acid (11.95g, 49.0mmol), O,N-dimethylhydroxylamine (4.88g, 50.0mmol), DCC (9.60 g, 50 mmol) and triethylamine (5.06 g, 50.0 mmol) in DMF (150 mL) was stirred overnight at room temperature. Water (500 mL) was added and the mixture was extracted with CHCl ₃ . The organic phase was washed with water, dried and concentrated under reduced pressure. Purification by flash chromatography (hexane/EtOAc, 1:1) gave [4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (8.50 g, 61% ). (c) (4-Formyl-cyclohexyl)-carbamic acid tert-butyl ester

A solution of [4-(methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester (7.50 g, 26.2 mmol) in dry ether (150 ml) was reduced with excess _LiAlH4 . The reaction mixture was quenched by careful addition of water and extracted with _CHCl3 . The mixture was dried and concentrated under reduced pressure to give (4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (6.30 g, 93%). (d) trans-[4-(benzylimino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester

(4-Formyl-cyclohexyl)-tert-butyl carbamate (3.80 g, 16.7 mmol), benzylamine (1.82 g, 16.7 mmol), acetic acid (0.01 g, 16.7 mmol) and anhydrous magnesium sulfate ( 4.01 g, 33.3 mmol) in dichloromethane (20 mL) was stirred for 5 days. The mixture was filtered through celite and concentrated under reduced pressure to give trans-[4-(benzylimino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (5.10 g, 97%) , a 97:3 trans:cis mixture. (e) trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester

A solution of trans-[4-(benzylimino-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (2.50 g, 8.00 mmol) and oxalic acid (0.80 g) in water/THF (50 mL, 1: The solution in 1) was stirred at room temperature for 10 hours. The reaction mixture was concentrated under reduced pressure and dichloromethane (50 mL) was added to the residue. The organic phase was dried and concentrated under reduced pressure to give trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.3 g, 80%). (f) trans-2-(4-tert-butoxycarbonylamino-cyclohexylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester

Butyllithium (1.6M in hexane, 5.0ml, 8.00mmol) was added dropwise to 4-benzyl 2-(diethoxy-phosphoryl)-succinate 1- tert-Butyl ester (3.21 g, 8.00 mmol) in THF (25 mL). After stirring at 0°C for 1 hour, the solution was transferred to a solution of trans-(4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (1.30 g, 5.72 mmol) in THF (10 mL). The resulting mixture was stirred at 0 °C for 1 hour and at room temperature overnight. Water was added and _the product was extracted with _CH2Cl2 . The organic phase was dried and concentrated under reduced pressure. Flash chromatography (Hexane/EtOAc, 80:20) gave trans-2-(4-tert-butoxycarbonylamino-cyclohexylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl base ester (1.10 g). (g) trans-2-(4-tert-butoxycarbonylamino-cyclohexylmethyl)-succinic acid 1-tert-butyl ester

Trans-2-(4-tert-butoxycarbonylamino-cyclohexylmethylene)-succinic acid 4-benzyl ester 1-tert-butyl ester (243 mg, 0.51 mmol) and palladium (5% loading (on charcoal) in ethanol (15 mL) was hydrogenated at 4 bar for 3 hours. The catalyst was removed from the reaction mixture by filtration. The catalyst was washed with ethanol and the solution was concentrated under reduced pressure to give crude trans-2-(4-tert-butoxycarbonylamino-cyclohexylmethyl)-succinic acid 1-tert-butyl ester (217 mg, >100%). (h) trans-2-(4-amino-cyclohexylmethyl)-succinic acid

To a solution of trans-2-(4-tert-butoxycarbonylamino-cyclohexylmethyl)-succinic acid 1-tert-butyl ester (200mg, 0.52mmol) in dichloromethane (1.32g, 15.6mmol) Triethylsilane (150 mg, 1.30 mmol) was added, followed by TFA (770 mg, 6.75 mmol). The reaction mixture was stirred for 2.5 hours, then concentrated under reduced pressure. Purification by HPLC (0-80% acetonitrile, 0.1% TFA in water) gave the title compound as TFA salt (60 mg, 34%). ¹ H NMR (500MHz, D ₂ O): δ0.99-1.11(m, 2H), 1.30-1.46(m, 4H), 1.54-1.62(m, 1H), 1.79-1.86(m, 1H), 1.89 -1.96 (m, 1H), 1.99-2.06 (m, 2H), 2.58-2.71 (m, 2H), 2.85-2.95 (m, 1H), 3.08-3.17 (m, 1H). MS(+)230(M+1). Example 16 2-(6-amino-pyridin-3-ylmethyl)-N-benzyl-N-hydroxyl-succinamic acid (a) N-benzyl-N-benzyloxy-2-(6- tert-Butoxycarbonylamino-pyridin-3-ylmethyl)-succinamic acid tert-butyl ester

To a solution _of 1-tert-butyl 2-(2-tert-butoxycarbonylamino-pyridin-4-ylmethyl)-succinate (0.67 g, 1.76 mmol) in _CH2Cl2 (25 mL) was added N-Benzyl-N-benzyloxyamine (0.42 g, 1.94 mmol), DCC (0.40 g, 1.94 mmol) and DMAP (0.02 g, 0.17 mmol) and the mixture was stirred overnight. Water was added and the mixture _was extracted with _CH2Cl2 . The organic phase was dried and filtered and the residue was purified by flash chromatography (hexane/EtOAc, 4:1) to give N-benzyl-N-benzyloxy-2-(6-tert-butoxycarbonylamino -pyridin-3-ylmethyl)-tert-butyl succinamic acid ester (0.51 g, 50%). (b) 2-(6-Amino-pyridin-3-ylmethyl)-N-benzyl-N-benzyloxy-succinamic acid

At 0°C, N-benzyl-N-benzyloxy-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-succinamic acid tert-butyl ester (1.0 g, 1.7 mmol) in dichloromethane (10 mL) was added TFA (4 mL). The reaction mixture was stirred for 4 hours, then concentrated under reduced pressure to give crude 2-(6-amino-pyridin-3-ylmethyl)-N-benzyl-N-benzyloxy-succinamic acid as TFA salt (0.9 g, 100%). (c) 2-(6-Amino-pyridin-3-ylmethyl)-N-benzyl-N-hydroxy-succinamic acid

2-(6-Amino-pyridin-3-ylmethyl)-N-benzyl-N-benzyloxy-succinamic acid (0.9 g, 1.7 mmol) and palladium (0.5 g, 5% were loaded on activated carbon above) in methanol (100 mL) was hydrogenated at 1 bar for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by flash chromatography ( _CHCl3 /MeOH/ _H2O , 10:5:1) to afford the title compound (123 mg, 22%). ¹ H NMR (600MHz, CD ₃ OD): δ2.50-3.03(m, 5H), 4.72(q, 2H), 6.65(d, 1H), 7.18-7.31(m, 6H), 7.53(d, 1H ), 7.65(s, 1H). MS(+)330(M+1). Example 17 2-(6-Amino-pyridin-3-ylmethyl)-3-[hydroxyl-(3-phenyl-propyl)-phosphono]-propionic acid (a) 2-(6-tert-butyl Oxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphono]-propionic acid ethyl ester

(3-Phenyl-propyl)-phosphinic acid (0.579 g, 3.143 mmol) and 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.327 g , 1.067 mmol) in MeCN (7.5 mL) was degassed using the freeze-thaw technique. BSA (2.55 g, 12.57 mmol) was added and the mixture was stirred for 3 days, concentrated under reduced pressure. The residue was dissolved in chloroform, washed with NaHCO ₃ and brine, dried and concentrated under reduced pressure. Flash chromatography (CH ₂ Cl ₂ /MeOH, 8:2) afforded 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl- Propyl)-phosphono]-propionic acid ethyl ester (0.240 g, 16%). (b) 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphono]-propionic acid

To 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxyl-(3-phenyl-propyl)-phosphono]-propionic acid ethyl ester (0.240g, 0.489 mmol) in MeCN (3 mL) was added LiOH (0.059 g, 2.45 mmol) in _H2O (3 mL). The mixture was then stirred at 20°C for 1.5 hours. Ethyl acetate was added and the mixture was washed with 1M HCl and brine, filtered to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl- Propyl)-phosphono]-propionic acid (0.174 g, 77%) as white crystals. (c) 2-(6-Amino-pyridin-3-ylmethyl)-3-[hydroxy-(3-phenyl-propyl)-phosphono]-propionic acid

At 4°C, 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-[hydroxyl-(3-phenyl-propyl)-phosphono]-propionic acid ( To a mixture of 0.170 g, 0.367 mmol) in ethyl acetate (3 mL) was slowly added ethyl acetate (4 mL, saturated with HCl(g)). The mixture was then stirred for 22 hours. Concentration under reduced pressure afforded the title compound (0.124 g, 93%) as the hydrochloride salt. ¹ H NMR (300MHz, CD ₃ SOCD ₃ ): δ1.52-1.72(m, 4H), 1.88-1.96(m, 2H), 2.47-2.49(t, 1H), 2.57-2.62(m, 2H), 2.77-2.82 (m, 2H), 6.94-6.97 (d, 1H), 7.15-7.29 (m, 4H), 7.75-7.80 (m, 2H), 8.05 (s, 1H). MS(+)363(M+1).

Example 18 2-(6-Amino-5-methyl-pyridin-3-ylmethyl)-3-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxyl-phosphono] -propionic acid (a) 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonomethyl]-3-(6-bis(tert-butoxycarbonyl) Amino-5-methyl-pyridin-3-yl)-propionic acid ethyl ester

2-(6-Bis(tert-butoxycarbonyl)amino-5-methyl-pyridin-3-ylmethyl)-acrylic acid ethyl ester (0.6g, 14.3mmol) and (1-benzyloxycarbonyl A solution of amino-2-methyl-propyl)-phosphinic acid (0.678 g, 2.5 mmol) in dry acetonitrile (10 mL) was degassed using the freeze-thaw technique. Bistrimethylsilylacetamide (5 mL, 20.3 mmol) was added under argon atmosphere. The resulting mixture was stirred at room temperature for 84 hours, then concentrated under reduced pressure. The remaining mixture was dissolved in chloroform and washed with saturated aqueous NaHCO ₃ . The aqueous phase was extracted with chloroform and EtOAc. The combined organic extracts were dried and concentrated under reduced pressure. The crude product was purified by flash chromatography (EtOAc/EtOH, 100:20 → 100:25) to give 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphono Methyl]-3-(6-bis(tert-butoxycarbonyl)amino-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (650 mg, 65.9%). (b) 2-[(1-Benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonomethyl]-3-(6-(tert-butoxycarbonylamino-5-methyl yl-pyridin-3-yl)-propionic acid

1M LiOH (2 mL) was added dropwise to 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonomethyl]-3-(6-bis(tert-butoxy Carbonyl)amino-5-methyl-pyridin-3-yl)-propionic acid ethyl ester (100 mg, 0.145 mmol) in acetonitrile (2 mL). The mixture was stirred overnight and concentrated under reduced pressure. The mixture was purified by column chromatography (isopropanol/conc. NH ₃ water/water, 4:2:1) to give impure product. The impure product was stirred with MeOH, filtered and concentrated under reduced pressure. The crude product was stirred with EtOH, filtered and concentrated under reduced pressure. The crude product was stirred with ethyl acetate/ethanol, filtered and concentrated under reduced pressure to give 2-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonomethyl ]-3-(6-tert-butoxycarbonylamino-5-methyl-pyridin-3-yl)-propionic acid (52 mg, 63.8%). (c) 2-(6-amino-5-methyl-pyridin-3-ylmethyl)-3-[(1-benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphono ]-propionic acid

2-[(1-Benzyloxycarbonylamino-2-methyl-propyl)-hydroxy-phosphonomethyl]-3-(6-tert-butoxycarbonylamino-5-methyl-pyridine A solution of -3-yl)-propionic acid (52 mg, 0.09 mmol) and ethyl acetate (6 mL, saturated with HCl(g)) was stirred for 20 min. The mixture was concentrated under reduced pressure, washed with acetonitrile and dissolved in ethanol and petroleum ether. The solution was concentrated under reduced pressure to obtain the title compound (41 mg, 91.3%) as hydrochloride. ¹ H NMR (600MHz, D ₂ O): δ0.99-1.05(m, 6H), 1.75-1.85(m, 1H), 2.10-2.28(m, 5H), 2.68-3.15(m, 3H), 3.75 -3.81 (m, 1H), 5.04-5.19 (m, 2H), 7.20-7.37 (m, 5H), 7.51-7.71 (m, 2H). MS(+)501(M+1).

Example 19 2-(6-amino-pyridin-3-ylmethyl)-3-methyl-succinic acid (a) 2-ethoxycarbonyl-3-methyl-succinic acid diethyl ester

A solution of diethyl malonate (2.44 g, 15 mmol) and cesium fluoride (2.32 g, 15 mmol) in DMF (20 mL) was stirred at room temperature under an atmosphere of argon for 1 hour. A solution of ethyl 2-methanesulfonyloxy-propionate (1.0 g, 5 mmol) in DMF (5 mL) was added and the mixture was stirred at 45 °C overnight. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated under reduced pressure. The crude product was purified by vacuum distillation. The product was purified by column chromatography (petroleum ether/ethyl acetate, 4:1) to obtain 2-(6-amino-pyridin-3-ylmethyl)-3-methyl-succinic acid (0.5 g, 37.7% ). (b) 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-ethoxycarbonyl-3-methyl-succinic acid diethyl ester

A solution of 2-(6-amino-pyridin-3-ylmethyl)-3-methyl-succinic acid (300 mg, 1.15 mmol) and NaH (30 mg, 1.25 mmol) in DMF (1 mL) was stirred at room temperature under argon atmosphere Stir for 1 hour. A solution of (5-bromomethyl-pyridin-2-yl)-tert-butylcarbamate (330 mg, 1.15 mmol) in DMF (1 mL) was added and the reaction mixture was stirred for 24 hours. The reaction was poured into water and extracted with ethyl acetate - the organic layer was washed with water, dried and concentrated under reduced pressure. The product was purified by column chromatography (petroleum ether/ethyl acetate, 4:1) to obtain 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-ethoxycarbonyl- 3-Methyl-succinic acid diethyl ester (220 mg, 40.9%). (c) 2-(6-Amino-pyridin-3-ylmethyl)-3-methyl-succinic acid

Diethyl 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-ethoxycarbonyl-3-methyl-succinate (94 mg, 0.20 mmol) in concentrated HCl (4 mL) was stirred overnight at reflux. The mixture was concentrated under reduced pressure and lyophilized to afford the title compound as HCl salt (50 mg, 90.3%). ¹ H NMR (400MHz, D ₂ O): δ1.22-1.35(m, 3H), 2.77-3.08(m, 4H), 6.99-7.05(d, 1H), 7.70(s, 1H), 7.84-7.91 (m, 1H). MS (+) 239 (M+1).

Example 20 2-(6-Amino-pyridin-3-ylmethyl)-3-phenethyl-succinic acid (a) 2-ethoxycarbonyl-3-phenethyl-succinic acid diethyl ester

A solution of diethyl malonate (240.2 mg, 1.5 mmol) and NaH (43.2 mg, 1.8 mmol) in THF (3 mL) was stirred at room temperature under argon atmosphere for 1 h. 2-(4-Nitro-benzenesulfonyloxy)-4-phenyl-butyric acid ethyl ester (590 mg, 1.5 mmol) and DMPU (192.2 mg, 1.5 mmol) were added and the mixture was stirred at room temperature for 3 days . The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The product was purified by column chromatography (petroleum ether/ethyl acetate, 4:1) to obtain 2-ethoxycarbonyl-3-phenethyl-succinic acid diethyl ester (274 mg, 52.1%). (b) 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-ethoxycarbonyl-3-phenethyl-succinic acid diethyl ester

A solution of 2-(6-amino-pyridin-3-ylmethyl)-3-phenethyl-succinic acid (9.3 mg, 0.027 mmol) and NaH (1.39 mg, 0.032 mmol) in DMF (0.5 mL) was stirred at room temperature Stir for 15 minutes. (5-Bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (8.76 mg, 0.031 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The product was purified by column chromatography (heptane/ethyl acetate, 2:1) to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-2-ethoxycarbonyl- 3-Phenylethyl-diethyl succinate (3.8 mg, 25.7%). (c) 2-(6-Amino-pyridin-3-ylmethyl)-3-phenethyl-succinic acid

2-(6-tert-Butoxycarbonylamino-pyridin-3-ylmethyl)-2-ethoxycarbonyl-3-phenethyl-succinic acid diethyl ester (94 mg, 0.169 mmol) in concentrated HCl (7 mL) The solution was stirred at reflux for 24 hours. The mixture was concentrated under reduced pressure and lyophilized to afford the title compound as HCl salt (55 mg, 99.2%). ¹ H NMR (400MHz, D ₂ O): δ1.63-1.98(m, 2H), 2.42-2.85(m, 4H), 3.00-3.60(m, 2H), 6.85-6.98(m, 1H), 7.10 -7.29 (m, 5H), 7.76-8.05 (m, 2H). MS(+)329(M+1).

Example 21 2-(6-amino-pyridin-3-ylmethyl)-3-butyl-succinic acid (a) 2-butyl-3-ethoxycarbonyl-succinic acid diethyl ester

A solution of diethyl malonate (3.589 g, 0.022 mol) and cesium fluoride (3.406 g, 0.024 mol) in DMF (50 mL) was stirred at room temperature under an atmosphere of argon for 1 hour. Ethyl 2-bromohexanoate (5 g, 0.022 mol) was added and the mixture was stirred at 100°C, then at 65°C overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The product was purified by column chromatography (heptane/ethyl acetate, 1:2) to give 2-butyl-3-ethoxycarbonyl-succinic acid diethyl ester (5.0 g, 73.8%). (b) 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-butyl-2-ethoxycarbonyl-succinic acid diethyl ester

A solution of 2-butyl-3-ethoxycarbonyl-succinic acid diethyl ester (1 g, 3 mmol) and NaH (119 mg, 5 mmol) in DMF (20 mL) was stirred at 0° C. under argon atmosphere for 60 min. (5-Bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.425 g, 5 mmol) was added and the mixture was stirred at room temperature for one week. Ethanol (1 mL) was added and the reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The product was purified by column chromatography (heptane/ethyl acetate, 4:1 to 1:1) to give 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-butane Diethyl-2-ethoxycarbonyl-succinate (1.2 g, 71.3%). (c) 2-(6-Amino-pyridin-3-ylmethyl)-3-butyl-succinic acid

Diethyl 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-3-butyl-2-ethoxycarbonyl-succinate (50 mg, 0.098 mmol) was dissolved in concentrated HCl ( 4 ml) solution was stirred at reflux for 24 hours. The mixture was concentrated under reduced pressure and lyophilized to afford the title compound as HCl salt (28 mg, 89.9%). ¹ H NMR (400MHz, D ₂ O): δ0.83-0.91 (m, 3H), 1.18-1.40 (m, 4H), 1.50-1.82 (m, 2H), 2.67-2.75 (m, 12H), 2.78 -2.85 (m, 2H), 2.89-3.03 (m, 1H), 6.97-7.09 (m, 1H), 7.63-7.67 (m, 1H), 7.80-7.85 (m, 1H). MS(+)281(M+1). Abbreviation Ac = Acetate aq = Aqueous AIBN = α,α'-Azoisobutyronitrile Bn = Benzyl BSA = N,O-bis(trimethylsilyl)acetamide Bu = Butyl Bz = Benzene Acyl DCC = dicyclohexylcarbodiimide DIAD = diisopropyl azodicarboxylate DIPEA = diisopropylethylamine DMAP = N,N-dimethylaminopyridine DME = 1,2-dimethoxy Ethane DMF = dimethylformamide DMSO = dimethyl sulfoxide EDC = 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide Et = ethyl EtOAc = ethyl acetate EtOH = Ethanol h = hour HMDS = hexamethyldisilazane HOAc = acetic acid HOBt = 1-hydroxybenzotriazole HPLC = high performance liquid chromatography KHMDS = potassium bis(trimethylsilyl)amide LDA = diiso Lithium propylamide Me = methyl MeOH = methanol min = minute PMB = 4-methoxybenzyl Ph = phenyl Pr = propyl PyBOP = hexafluorophosphate (benzotriazol-1-yloxy)tri Pyrrolidinylphosphonium TEA = triethylamine TFA = trifluoroacetic acid THF = tetrahydrofuran TMSCN = trimethylsilyl cyanide Tos = toluene-4-sulfonyl.

Claims (17)

1. the compound of a general formula I Or its pharmacy acceptable salt or solvate, or the solvate of this salt, wherein R ₁Representative,

By the C of one or more basic groups as amino, amidino groups and/or guanidine radicals replacement ₁-C ₆Alkyl;

By the cycloalkyl of one or more basic groups as amino, amidino groups and/or guanidine radicals replacement;

The heterocyclic radical that contains at least one nitrogen-atoms;

The heterocyclic radical that contains at least one heteroatoms that is selected from S or O and replace as amino, amidino groups and/or guanidine radicals by one or more basic groups;

Or by the aryl of one or more basic groups as amino, amidino groups and/or guanidine radicals replacement, R ₂Represent H, acyl group, amido, alkyl, alkyl-carbamoyl, alkylthio, alkoxyl group, aroyl, aroylamino, aryloxy, arylthio, amidino groups, amino, aryl, formamyl, carboxyl, cyano group, cycloalkyl, formyl radical, guanidine radicals, halogen, heterocyclic radical, hydroxyl, oxo, nitro, thiol, Z ₂N-CO-O-, ZO-CO-NZ-or Z ₂The N-CO-NZ-group, R ₃Represent COOR ₅, SO (OR ₅), SO ₃R ₅, P=O (OR ₅) ₂, B (OR ₅) ₂, P=OR ₅(OR ₅) or the isostere of tetrazolium or any carboxylic acid, R ₄Representative

Group or

Group or

Group, R ₅Represent H, C ₁-C ₆Alkyl or aryl, R ₆Represent C ₁-C ₆The H that alkyl, aryl, cycloalkyl, heterocyclic radical or optional N-replace ₂N-C (Z)-CONH-C (Z)-or H ₂N-C (Z)-group, R ₇Represent H or C ₁-C ₆Alkyl, X are represented O, S, SO, SO ₂, C (Z) ₂, N (Z), NR ₇SO ₂, SO ₂NR ₇, NR ₇CO or CONR ₇, Y represents O, N (Z), S, C (Z) ₂Or singly-bound, Z independently represents H, C ₁-C ₆Alkyl, aryl, cycloalkyl or heterocyclic radical, condition are to represent O, S, SO, SO as X ₂, N (Z), NR ₇SO ₂, SO ₂NR ₇Or NR ₇During CO, then Y represents C (Z) ₂Or singly-bound.

2. the solvate of the compound of claim 1, or its pharmacy acceptable salt or solvate or its salt, wherein R ₁Representative,

By the cycloalkyl of one or more basic groups as amino, amidino groups and/or guanidine radicals replacement;

The heterocyclic radical that contains at least one nitrogen-atoms;

The heterocyclic radical that contains at least one heteroatoms that is selected from S or O and replace as amino, amidino groups and/or guanidine radicals by one or more basic groups; R ₂Represent H, C ₁-C ₃Alkyl, amino, halogen, hydroxyl, R ₃Represent COOR ₅, R ₄Representative Group, R ₅Represent H, C ₁-C ₆Alkyl or aryl, R ₆Represent C ₁-C ₆The H that alkyl, aryl, cycloalkyl, heterocyclic radical or optional N-replace ₂N-C (Z)-CONH-C (Z)-or H ₂N-C (Z)-group, X represent C (Z) ₂, Y represents O or C (Z) ₂, Z independently represents H or C ₁-C ₆Alkyl.

3. the solvate of the compound of claim 1, or its pharmacy acceptable salt or solvate or its salt, wherein R ₁Representative,

By the cycloalkyl of one or more basic groups as amino, amidino groups and/or guanidine radicals replacement;

The heterocyclic radical that contains at least one nitrogen-atoms;

The heterocyclic radical that contains at least one heteroatoms that is selected from S or O and replace as amino, amidino groups and/or guanidine radicals by one or more basic groups; R ₂Represent H, C ₁-C ₃Alkyl, amino, halogen or hydroxyl, R ₃Represent COOR ₅, R ₄Representative

Group, R ₅Represent H, C ₁-C ₆Alkyl or aryl, R ₇Represent H or C ₁-C ₆Alkyl, X are represented C (Z) ₂, Y represents C (Z) ₂Or singly-bound, Z independently represents H or C ₁-C ₆Alkyl.

4. the solvate of the compound of claim 1, or its pharmacy acceptable salt or solvate or its salt, wherein R ₁Representative,

By the cycloalkyl of one or more basic groups as amino, amidino groups and/or guanidine radicals replacement;

The heterocyclic radical that contains at least one nitrogen-atoms;

The heterocyclic radical that contains at least one heteroatoms that is selected from S or O and replace as amino, amidino groups and/or guanidine radicals by one or more basic groups; R ₂Represent H, C ₁-C ₃Alkyl, amino, halogen or hydroxyl, R ₃Represent COOR ₅, R ₄Representative

Group, R ₅Represent H, C ₁-C ₆Alkyl or aryl, X are represented C (Z) ₂, Y represents C (Z) ₂Or singly-bound, Z independently represents H or C ₁-C ₆Alkyl.

5. a method for preparing each compound among the claim 1-4, wherein R ₁, R ₅, R ₆With Z as defined in claim 1 and R ₂Be H, R ₃Be COOR ₅, R ₄Representative

Group, X are C (Z) ₂, Y is C (Z) ₂, this method comprises the following steps: to make the compound of general formula VI

R wherein ₁With Z as defined in claim 1, X is C (Z) ₂With Y be C (Z) ₂, with the compound of formula IX

R ₆PO ₂H ₂(IX) R wherein ₆As defined in claim 1, in the presence of suitable reagent such as BSA or HMDS, under standard conditions, react.

6. a method for preparing each compound among the claim 1-4, wherein R ₁, R ₂, R ₅, R ₆With Z as defined in claim 1, R ₃Be COOR ₅, X is C (Z) ₂, Y is O, R ₄Representative

Group, this method comprises the following steps: to make the compound of general formula X II, R wherein ₁And R ₂Be C (Z) with X as defined in claim 1 ₂, with the compound of general formula X III

R ₆PO ₃H ₂(XIII) R wherein ₆As defined in claim 1, at suitable coupling reagent such as DCC/DMAP, PyBop/DIPEA or SOCl ₂Exist to descend, under standard conditions, react.

7. a method for preparing each compound among the claim 1-4, wherein R ₁And R ₂As defined in claim 1, X and Y are C (Z) ₂Or singly-bound, R ₃And R ₄Be COOR ₅, this method comprises the following steps: to make the compound of general formula X IV

R wherein ₂And R ₅Be C (Z) with Y as defined in claim 1 ₂Or singly-bound, with the compound of general formula III,

R ₁-X-L (III) is R wherein ₁As defined in claim 1, X is C (Z) ₂With L be suitable leavings group such as Cl, Br, I or tosyl group, in the presence of suitable alkali such as LDA or NaH, under standard conditions, react.

8. a method for preparing each compound among the claim 1-4, wherein R ₁, R ₂, R ₅, R ₇, X, Y and Z as defined in claim 1, R ₃Be COOR ₅And R ₄Representative

Group, this method comprises the following steps: to make the compound of general formula X V

With the compound of general formula X VI,

HR ₇NOH (XVI) is R wherein ₇As defined in claim 1, in the presence of suitable reagent such as DCC/DMAP, under standard conditions, react.

9. medicinal preparations, it contains as each compound among the claim 1-4 of activeconstituents in conjunction with pharmaceutically acceptable auxiliary, diluent or carrier.

10. each the purposes of compound in treatment among the claim 1-4.

11. each compound is used for suppressing the purposes of the medicine of carboxypeptidase U among the claim 1-4 in preparation.

12. a method that is used for the treatment of or prevents and suppress carboxypeptidase U diseases associated, this method comprise the Mammals that needs this treatment comprise human significant quantity as each defined compound among the claim 1-4.

13. a medicinal preparations that is used for the treatment of or prevents and suppress carboxypeptidase U diseases associated, said preparation comprise as each defined compound among the claim 1-4 in conjunction with pharmaceutically acceptable auxiliary, diluent or carrier.

14. medicinal preparations, said preparation comprises: (i) solvate of the compound of formula I or its pharmacy acceptable salt or solvate or this salt, and with (ii) one or more have antithrombotic drug such as antiplatelet drug, thromboxane acceptor inhibitor, synthetase inhibitors, fibrinogen receptor antagonist, prostacyclin mimetics, phosphodiesterase inhibitor or the ADP-acceptor (P of different mechanism of action ₂T) antagonist, and the pharmaceutically acceptable auxiliary of blended, diluent or carrier with it.

15. one kind comprises the test kit as the lower section: (i) a kind of medicinal preparations, said preparation comprise the solvate of the compound of formula I or its pharmacy acceptable salt or solvate or this salt and the pharmaceutically acceptable auxiliary of blended, diluent or carrier with it; (ii) a kind of medicinal preparations, said preparation comprise one or more antithrombotic drugs with different mechanism of action such as antiplatelet drug, thromboxane acceptor inhibitor, synthetase inhibitors, fibrinogen receptor antagonist, prostacyclin mimetics, phosphodiesterase inhibitor or ADP-acceptor (P ₂T) antagonist, and the pharmaceutically acceptable auxiliary of blended, diluent or carrier with it; (ii) each provides with the form that is fit to give together with another composition for described compound (i) and medicine.

16. a treatment suffers from or susceptible wherein needs or require to suppress carboxypeptidase U and different antithrombotics forms patient's the method for the disease of mechanism, this method comprises and gives the effective total amount of this patient: (i) solvate of the compound of formula I or its pharmacy acceptable salt or solvate or this salt and the pharmaceutically acceptable auxiliary of blended, diluent or carrier with it; And in conjunction with (ii) one or more have antithrombotic drug such as antiplatelet drug, thromboxane acceptor inhibitor, synthetase inhibitors, fibrinogen receptor antagonist, prostacyclin mimetics, phosphodiesterase inhibitor or the ADP-acceptor (P of different mechanism of action ₂T) antagonist, and the pharmaceutically acceptable auxiliary of blended, diluent or carrier with it.

17. a treatment suffers from or susceptible wherein needs or require to suppress carboxypeptidase U and different antithrombotics forms patient's the method for the disease of mechanism, this method comprises and gives this patient preparation as defined in claim 15.